In recent years the production of proteins has steadily increased and it is likely that proteins will become the biggest group of therapeutics available for the treatment of various diseases in the near future. The impact of proteins emerges from their specificity, such as the specific target recognition and binding function.
Cell cultures are used in fermentative processes to produce substances and in particular proteins. A distinction is made between processes in which the cell cultures are genetically unmodified and form their own metabolic products and processes in which the organisms are genetically modified in such a manner that they either produce a larger amount of their own substances such as proteins or produce foreign substances. The organisms producing the substances are supplied with a nutrient medium which guarantees the survival of the organisms and enables the production of the desired target compound. Numerous culture media are known for these purposes which enable an optimal cultivation of the specific host.
High-cell-density cultivation of Escherichia coli is reported by Riesenberg (Riesenberg, D., et al., Curr. Opin. Biotechnol. 2 (1991) 380-384) and Horn (Horn, U., et al., Appl. Microbiol. Biotechnol. 46 (1996) 524-532). Riesenberg, D. and Guthke, R. (Appl. Microbiol. Biotechnol. 51 (1999) 422-430) reported the high-cell-density cultivation of microorganisms. Growing E. coli to high cell density is reviewed by Shiloach, J. and Fass, R. (Biotechnol. Advances 23 (2005) 345-357).
In WO 91/10721 a process for high cell density fermentation of Escherichia coli in an agitated boiler fermenter is reported. A method of plasmid DNA production and purification is reported in WO 97/29190. The controlling of growth of aerobic submerged microorganism cultures by controlling dissolved oxygen concentration and oxygen transfer rate is reported in DD 295867. In EP 0 866 876 a process for the preparation of recombinant proteins in E. coli by high cell density fermentation is reported.
In WO 03/048374 a process for the production of aromatic amino acid metabolite or derivative thereof is reported. A process for the preparation of recombinant proteins in E. coli by high cell density fermentation is reported in WO 97/21829.